Effect of age on the risk of immune-related adverse events in patients receiving immune checkpoint inhibitors

Identifying patients at increased risk of immune-related adverse events (irAEs) facilitates safe application of immune checkpoint inhibitors (ICIs). This retrospective study aimed to determine the effect of age on the risk of irAEs in patients receiving ICIs and to identify potential mechanisms underlying age-related irAE risk differences. We analyzed reports of FDA Adverse Event Reporting System from July 1, 2014, to September 30, 2021. The information component ratio (IC Delta) was used to compare the irAE risk between older adults (> 65 years) and younger adults (25-65 years), of which the 95% confidential interval lower limit (IC Delta 025) exceeding zero indicated significantly increased risk. We found that older adults had a significantly higher overall irAE risk than younger adults (IC Delta 025 0.38), which was observed in almost all organ systems. We further analyzed the correlation between age-related irAE risks and age-related transcriptional changes to identify potential genes and pathways underlying age-related irAE risk differences. We found that genes significantly correlated with IC Delta were enriched in processes including extracellular matrix organization, regulation of myeloid leukocyte mediated immunity, and regulation of c-Jun N-terminal kinase (JNK) cascade. In addition, single-cell RNA sequencing analysis confirmed that genes involved in collagen-containing extracellular matrix and JNK cascade were significantly upregulated in myeloid cells from ICI-associated colitis tissues compared with ICI-treated colon tissues without colitis. In conclusion, older adults receiving ICIs have higher irAE risks than younger adults. Upregulation of genes involved in JNK cascade and collagen-containing extracellular matrix in myeloid cells may contribute to increased irAE risks in older adults.